Insights into the interactions of zinc-phthalocyanines with lipid bilayers for liposomal formulations

Phthalocyanines (Pcs) are promising photosensitizers for photodynamic therapy (PDT). Inclusion into liposomes helps increase their bioavailability due to their hydrophobic nature. In order to elucidate the molecular interactions between Pcs and lipids employed in liposomal formulations, comprehensive computational simulation studies of zinc-phthalocyanine (ZnPc) and its tetraamino derivative (TaZnPc) were carried out. Initially, unbiased molecular dynamics (MD) simulations were performed. It was found that both Pcs freely insert into the pure DPPC bilayer in the liquid phase (55 °C). However, the inclusion of 30% cholesterol into the bilayer significantly altered their behavior. While ZnPc incorporates on the nanosecond timescale, TaZnPc´s insertion was notably delayed, being observed after several hundred ns, up to almost one μs of simulation. Additionally, the mobility of the Pcs inside the membrane was affected as well. Free energy profiles computed using the umbrella sampling method show that insertion of both ZnPc and TaZnPc into these bilayers is a thermodynamically favored barrierless process. The differences observed between the Δ<em>G</em>(<em>z</em>) profiles were ascribed to the presence of four polar amino groups in TaZnPc. This study provides insights for optimizing liposomal formulations to enhance drug delivery efficiency and membrane stability.